BettER: Biomarker Driven Early Therapeutic Selection in Patients With HR+ HER2- Metastatic or Unresectable Breast Cancer

This is a prospective study to assess the impact of biomarker driven, early therapeutic switching and delayed imaging with the incorporation of DiviTum® serum TK1 activity ("DiviTum® TKa") in patients with hormone receptor (HR) positive, HER-2 negative metastatic or unresectable breast cancer receiving first-line or second-line treatment.

Inclusion Criteria - Patients * Diagnosis of metastatic or advanced unresectable invasive breast cancer with MD intent to treat as HR-positive and HER2-negative, with the following arm-specific requirements: * Arm 1: Patient must be planning to initiate standard of care first-line therapy with FDA-approved endocrine therapy plus CDK4/6 inhibitor for the stated diagnosis at the time of study enrollment. Note: Ribociclib is the preferred CDK4/6 inhibitor, but alternative CDK4/6 inhibitors are allowed. Note: Initiation of endocrine therapy prior to ultimate plan for addition of CDK4/6 inhibitor is permitted prior to enrollment. * Arm 2: patient must be planning to initiate standard of care second-line therapy with FDA-approved endocrine therapy plus CDK4/6 inhibitor for the stated diagnosis at the time of study enrollment. Triplet regimens are permitted as long as they contain CDK4/6 inhibitor and endocrine therapy. Note: Initiation of endocrine therapy prior to ultimate plan for addition of CDK4/6 inhibitor is permitted prior to enrollment. * Arm 3: patient must be planning to initiate first- or second-line therapy for the stated diagnosis at the time of study enrollment with therapy other than endocrine therapy plus CDK4/6 inhibitor. * Any prior therapy for early stage breast cancer is allowed, including endocrine therapy and chemotherapy. * Prior receipt of adjuvant CDK 4/6 inhibitor therapy is permitted with the following arm-specific requirements: * Arm 1: CDK4/6 inhibitor may have been given only in the neoadjuvant/adjuvant setting (not metastatic setting), and the last dose must have been \> 12 months prior to study enrollment. * Arms 2 and 3: No restrictions on prior CDK4/6 inhibitors. * Measurable or non-measurable disease per RECIST v1.1. * At least 18 years of age. * ECOG PS ≤ 2 * Post-menopausal status, defined as one of the following: * Age ≥ 60 years * Age \< 60 with intact uterus and amenorrhea for 12 consecutive months or more * Status post bilateral oophorectomy, total hysterectomy * Pre- or peri-menopausal with suppressed ovarian function by use of GnRH agonist/antagonist or surgical bilateral oophorectomy * Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria - Patients * Receipt of any prior cytotoxic chemotherapy line for metastatic disease. There will be no limit to chemotherapy use in the neoadjuvant or adjuvant setting. * Prior or concurrent malignancy (unless that malignancy's natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen). * Arms 1 and 2: Concurrent participation in any investigational therapeutic trial for treatment of metastatic breast cancer. Eligibility Criteria - Physicians * Medical Oncologist at Siteman Cancer Center. * Treating patients with metastatic or advanced unresectable breast cancer. * Willing to complete Physician Surveys during participation.